Over 40 million Americans over the age of 50 (14 million of which are men) are afflicted with low bone density or osteoporosis and its associated increased risk of fractures. Individuals with osteoporotic fractures are prone to depression, dependency and increased mortality. While aging is a major cause of osteoporosis, disease, disuse, and certain drugs can also cause bone loss at any stage in life.
The skeleton is a highly organized system that supports the body's weight, houses mesenchymal and hematopoetic stem cells, and serves as a calcium reservoir. The structure of bone comprises an outer cortical dense shell and an inner trabecular bone meshwork. Exercise can increase trabecular bone mineral density (BMD), and bone volume fraction (BVF), trabeculi thickness, and cortical BMD and thickness. In contrast, disease, disuse, and certain drugs (such as glucocorticoids) can decrease these parameters and cause osteoporosis in both males and females. Osteoporosis is defined by a reduction in bone mass (more than 2.5 standard deviations (SD) below average) and altered bone micro-architecture (such as decreased trabeculi thickness). With decreasing bone mass there is an increased risk of bone fractures. Thus, at the point of being diagnosed as osteoporotic, a patient has a 16-fold increase in fracture risk compared to someone with normal bone density. Fractures are associated with depression, dependency, and increased mortality (greater than 25% within 12 months for the elderly) and hip fractures account for over 50,000 deaths annually (National Osteoporosis Foundation (NOF) statistic). While osteoporosis is less prevalent in men, over 30% of hip fractures occur in men and mortality rates are greater for males compared to females. Currently, over 20 billion dollars are spent in the US and 30 billion dollars in the European Union to cover the direct costs of osteoporosis. Of even greater concern, it is estimated that by 2020 more than 61 million men and women in the US, over the age of 50, will have low bone density or osteoporosis (NOF statistic), and finding effective novel treatments is therefore a priority. In fact, one in three women over the age of 50 will experience an osteoporosis related fracture in their lifetime. Along with its associated increase in fracture risk, bone loss may have negative effects on metabolism and insulin secretion. Despite all the available treatments on the market, the number of osteoporotic patients is on the rise in the U.S. and worldwide. There are several reasons for this, including a lack of awareness that one is at risk early in life, an increasing elderly population, and patient noncompliance due to unwanted medication side effects. In addition, conventional bone loss treatments are not always effective. Currently there are no alternative or natural treatments that can be used in place of osteoporosis medicines for people with low bone density or osteoporosis. Therefore, doctors are looking for new approaches to increase bone density in their patients and companies are working to improve pharmacologic bone therapeutic drugs.
Certain people are more likely to develop osteoporosis than others, some risk factors are:                Being female        Older age        Family history of osteoporosis or broken bones        Being small and thin        Certain race/ethnicities such as Caucasian, Asian, or Hispanic/Latino although African Americans are also at risk        History of broken bones        Low levels of sex hormones        Low estrogen levels in women, including menopause        Missing periods (amenorrhea)        Low levels of testosterone and estrogen in men        Diet                    Low calcium intake            Low vitamin D intake            Excessive intake of protein, sodium and caffeine                        Inactive lifestyle        Smoking        Alcohol abuse        Certain medications such as steroid medications, some anticonvulsants and others        Certain diseases and conditions such as anorexia nervosa, rheumatoid arthritis, gastrointestinal diseases and others        
Menopausal women are prone to losing bone during menopause time due to decreased estrogen levels. Even during perimenopause (the period of 2 to 8 years before menopause) estrogen levels may start to drop off. Over time, too much bone loss can first cause oteopenia (low bone mass) and then osteoporosis.
Diagnosis of type 1 diabetes (T1D) is increasing in children and adults. While medical advances are extending patient lifespan, maintaining euglycemia remains difficult, even under therapeutic vigilance. Thus, more T1D patients (males and females) are suffering from complications, including bone loss. This means that patients begin aging/menopause with an already increased fracture risk. Once fractures occur, they can be difficult to heal, require extended hospitalizations, reduce the quality of life and increase mortality. Poor bone health also negatively affects the entire body. Postmenopausal women with T1D diabetes have higher incidences of osteoporotic fractures than women without diabetes. Children with T1D have lower bone mineral density than children without diabetes. Thus, maintaining bone health is critical for the overall quality of life of T1D patients and important for maximizing therapeutic/curative treatments involving marrow immune/progenitor cells since marrow cells and bone cells communicate.
Type 2 Diabetes (T2D) patients are also at higher risk of osteoporotic fractures than non-diabetics.
The two key components to strengthening bone and preventing osteoporosis are 1) attaining maximum bone density and 2) preventing bone loss during adulthood and aging. Bone remodeling occurs because bone is dynamic and constantly adapts to environmental cues to form or resorb bone. Targeted bone remodeling through the activities of osteoblasts (bone forming cells) and osteoclasts (bone resorbing cells) maintains blood calcium levels within a critical range while keeping bone strong at sites where support is needed. When formation and resorption activities are in balance there is no net gain or loss of bone, however when formation is decreased and/or resorption is increased then bone loss ensues.
Increased osteoclast activity results in bone resorption. Osteoclasts are derived from hematopoetic stem cells. These cells give rise to cells of the monocyte/macrophage lineage which, under the right conditions, develop into osteoclast precursors. Further signaling through factors such as RANKL (located on osteoblast surfaces) stimulate osteoclast maturation. Mature osteoclasts express enzymes involved in bone matrix degradation (including cathepsin K and TRAP5b).
Increased osteoblast activity results in bone formation, which can be regulated at several levels including 1) lineage selection, 2) maturation and 3) death. Because bone marrow stromal cells (BMSC) give rise to osteoblasts, adipocytes and other cell types, selection of one lineage (adipocytc) could be at the cost of another (osteoblast). This is supported by the reciprocal relationship between bone adiposity and mineral density recognized with aging, limb unloading, cell culture models, and type I (T1) diabetes. Osteoblast activity can be further regulated through death/apoptosis. An increase in osteoblast death will result in fewer bone making cells and therefore bone loss. Examples include the rapid bone adaptation to disuse/unloading, which results in bone loss, increased marrow adiposity, and increased bone cell death. Aging also increases bone cell apoptosis. Many factors contribute to modulating some or all aspects of osteoblast regulation (lineage, maturation, death) including: positive factors such as TGFβ, bone morphogenic proteins (BMPs), parathyroid hormone (PTH), and Wnts and negative factors such as cytokines.
Bisphosphonates are one of the most common treatments for osteoporosis. These compounds incorporate into the bone mineral and inhibit bone catabolism by osteoclasts and are effective at reducing fractures. However, many of these compounds need to be taken on an empty stomach and can cause gastric reflux and nausea resulting in reduced patient compliance. There is also concern about the length of time that these compounds reside in bone and their long-term impact on bone remodeling and strength. Selective estrogen receptor modifiers (SERMS) are another therapeutic treatment, but they still carry some concerns with regard to cancer. Hormone replacement therapy has been studied as useful in preventing or slowing the occurrence of osteoporosis, but sustained use of hormone replacement over many years may increase women's risk of breast cancer, may increase incidence of venous thrombosis (blood clots), exacerbation of pre-existing liver diseases and an increased risk of endometrial cancer as well as hypertension. Amgen has a drug under development (that is similar to osteoprotegrin) that works by modifying the RANKL/RANK system and hence suppresses osteoclast activity. Intermittent PTH treatment is an anabolic treatment, but this intravenous treatment is expensive and only indicated for severe osteoporotic patients. Taken together, it is not surprising that many people diagnosed with low bone density are confused about what to do. Many people do not want to take medication for fear of long-term effects. While weight bearing exercise and adequate calcium intake are two natural approaches, they cannot always overcome effects of disease, medications, and aging.